Several chronic and acute degenerative disorders of the central nervous system (CNS) show as part of their pathology the presence of reactive brain macrophages or microglial cells. These microglial cells are associated with the pathological lesions of the disease in question. It has been suggested that the presence of these cells is either the cause of these diseases, or that microglia play a major role in their progression and outcome. The presence of microglial cells in these disease states is suggested to indicate an inflammatory or immune response within the brain.
Many human neurodegenerative disorders are characterized by such physical and biochemical pathology. Of these, Alzheimer's disease (AD) is the most common, characterized by a progressively worsening and debilitating dementia.
Alzheimer's disease affects millions of individuals of all races and ethnic backgrounds. The number of sufferers is expected to expand markedly as the proportion of the aged in the population increases (Plum, 1979). While some intellectual dysfunction is a natural result of the aging process, the dementia caused by AlzheimerIs disease is by no means normal. After onset of the disease, life expectancy ranges from only five up to twenty years.
There is presently no treatment that will arrest the progression of Alzheimer's disease. Clinical trials have been instigated involving the use of agents from such diverse pharmaceutical classes such as cerebral vasodilators, CNS stimulants, neuroleptics, nootropics, receptor stimulants, neuropeptides, aminergic enhancers and cholinergic enhancers. The results of these trials have all been disappointing to date.
The brains of individuals suffering from AD are characterized by prominent neuropathologic lesions, such as neurofibrillary tangles (NFTS), neuropil threads (NT) and amyloid-rich senile plaques (SP). These lesions are associated with massive loss of populations of CNS neurones and their development invariably accompanies the clinical dementia associated with AD. Thus, the reproduction of such lesions in an animal would provide a valuable model for the study of the development and progression of AD. Equally, the model would also provide for the screening of putative prophylactic and therapeutic compositions. Szczepanik et al., 1996 have reported an acute inflammatory response and the formation of necrotic lesions upon intrahippocampal infusion of lipopolysaccharides. Such a system is, however, unsuitable as a model for the chronic inflammatory response observed in AD.
At present, the only source f or study of the physical manifestations of AD in the CNS is from cadaver specimens. Although useful from an anatomical perspective, such material can provide little indication of the early progression of AD and is of no use in the design of therapies to counter the development of the lesions. Thus, prospective models of NFT and SP development that may or may not form the basis for the targeting of prophylactic pharmaceuticals are impossible to validate or disprove.
There is thus a great need for animal models of CNS diseases, conditions and disorders. There is also a need for animals that develop or mimic similar pathology and symptoms to those manifested in human sufferers and for a method that identifies compounds useful in the generation of such a model.
Such a model would be invaluable in the evaluation, of prospective treatments for CNS disease, including the assessment of therapeutic or prophylactic pharmaceutical preparations, or alternative non-invasive strategies. Suitable diseases that could be studied by such a technique include any whose symptoms are manifested through chronic cerebral inflammation. Examples include Alzheimer's type senile dementia, Lewy Body dementia, Parkinson's disease, Multiple sclerosis, transmissible spongiform encephalopathies, motor neuron disease and viral encephalopathies.